A Review On 3D Printing Technologies for Drug Delivery in Pharmaceuticals

The idea of "personalized medicine" has garnered a lot of interest lately as a way to tailor therapy to each patient's requirements. The potential for personalized care for every patient is made possible by technological advancements! The effectiveness of individualized therapy is influenced Several factors contribute to this, including, individual biological difference, differences in living and working environments, interactions between drugs and herbs and foods, and various illnesses. Therefore, it's critical to develop a universal process To create compositions it, according to specific needs, may distribute drugs without the right characteristics. Three-dimensional  printing technology has the capability to precisely manage the space and dispense small amounts of medication for personalized drug administration. 3D printing technology has been thoroughly studied The landscape of drug delivery has evolved significantly since the FDA approved the first levetiracetam 3D-printed tablet, known as Spritam^[1,2]. 3D printing is a method that constructs a three-dimensional object incrementally from a digital design. This innovative technique, initially introduced for rapid prototyping in the early 1990s, involves the sequential deposition of multiple layers to create solid forms. Originating over three decades ago from advancements in chemistry, optics, and robotics, this method was originally employed to produce models using UV-cured resin ^[3,4]. In its simplest form, a 3-D printer uses computer-aided design and programming to create three-dimensional objects by layering substance onto a basis. Initially, To create the component's a basis, the material is extruded onto the x and y planes from the printer's head. Subsequently, a liquid binder is applied to this base as the printer moves along the z-axis, building up to the required thickness. Although the process is executed repeatedly following the computer's directives, Layer after layer, the item is built gradually. Following a treatment procedure that gets rid of any unbound molecules, the finished product is finished. Pharmaceutical dose forms that are highly reproducible and carefully regulated may be produced using this 3D printing technique. Software for electronic design is used to create. Objects of any dimensions. However, this might be mistaken with additive processes like film lamination, coating, and capsule filling in pharmaceutical manufacture. Biomedical, pharmaceutical, construction, architecture, and aerospace are just Several current and emerging industries are heavily utilizing 3D printing technology.The manufacturing sector has been using it for decades. Small-scale production processes like prototyping, customization, producing complicated items, and democratizing ideas that are frequently challenging to build using conventional techniques can all benefit from this. In addition, it reduces energy and material waste, speeds up time to market, promotes environmental sustainability, and eventually lowers production costs. Scientists are now eager to transform the pharmaceutical and healthcare sectors by using 3DP technology to the large-scale manufacturing of medicinal dosage forms.^[5] 3D printing is increasingly utilized across various industries, with its applications continually expanding. The concept of 3D printing was first introduced in the 1970s, utilizing a high-energy beam to construct objects layer by layer by solidifying powdered materials. This method is referred to as "selective laser sintering." Subsequently, during the 1980s and 1990s, new printing techniques such as fused deposition modeling (FDM) and stereolithography (SLA) emerged. Initially, the automotive and aerospace industries adopted 3D printing to enhance the prototyping process. Over time, its applications have broadened to encompass fields such as jewelry, art, education, and construction ^[6,7].  Because of its ability to create tailored medication that can achieve the best possible therapeutic results with the fewest possible adverse effects, 3D printing is becoming more and more popular in pharmaceutical and medical research and application. In addition to customized medicine dosage forms, many advanced drug delivery systems, including prolonged drug release, fixed dose combination, and gastro-retentive platforms, have been created utilizing various 3D printing methods ^[8,9]. A variety of innovative floating medicine delivery system designs created using 3D printing have been created and released in recent years ^[10,11]. The challenges associated with traditional methods of preparing floating drug delivery systems, such as tableting and coating—particularly the difficulty in adjusting doses due to the inability to break tablets—can be effectively resolved through this printing technique. Additionally, because each patient has a varied stomach emptying interval, the medication is delivered at various body locations in each patient. Therefore, customized dosage forms and preparation are required for floating medication delivery systems. This review explains how to build a gastro-retentive medication delivery system using 3D printing technology. The preparation methods for floating medication delivery systems—both conventional and innovative—are examined and updated. The benefits and areas for development of the floating medication delivery devices made using 3D printing are examined and addressed. Lastly, the writers' thoughts regarding the viability and future of 3D printing are explored.^[12]

Over the last fifteen years, the pharmaceutical business has used a number Various methods of 3D printing.

Pharmaceutical dosage forms are manufactured using a variety of techniques for 3D printing. Four of the most widely used methods of three-dimensional printing are light introduction polymerization, liquid dispersion on powder, FDM 3D thermal inkjet (TIJ), and several more have been created.

1. Fused deposition modelling:

The procedure comprises selecting the suitable thermoplastic polymer, melting it, and then extruding it via a movable, heated nozzle. The molten polymer is added layer by layer. It then takes on the desired shape that was created using computer-aided design models. This approach may be applied to dosage forms that incorporate polymers, such as implants and constant-drug-release tablets. There are several advantages to FDM 3D printing. FDM printers, for example, are fairly priced, and the materials they use are widely available and economically priced. Furthermore, printing precision alone may be used to swiftly make high-detail goods. Because of their limitations in terms of feature complexity, FDM printers work best with finer models or professional-quality prototypes can generate ^[13].

This technique generates a vapour bubble by heating the ink fluid using a micro-resistor, which forces the ink to drop out of the nozzle. Pneumatic extrusion and drop-on-demand inkjet printing are the terms for these processes. The 3D TIJ differs from other printers in that it can print liquid with a range of properties. Medical preparations and solutions have been distributed spontaneously using this technique. It can also be used in the production of medicinal goods ^[14].

This powder-based 3D printing technique involves spraying or dropping different mixes of ink and active chemicals in varying droplet sizes onto a powder substrate, which then solidifies into a solid dose form. This technique's benefit is its capacity for large-scale expansion. Additionally, the substance is porous and low in density, which makes it perfect for creating dosage forms for tablets that dissolve quickly. An example of a final product with a smooth exterior is Zip Dose. For this reason, grinding is usually not required ^[15].

Light-induced polymerization is a three-dimensional printing technique that solidifies light-sensitive polymers or radiation-curable resins one layer at a time using light or ultraviolet (UV) radiation. It has developed into a number of sophisticated 3D printing methods, including as SLA, digital light processing, and continuous direct light processing, and is currently used to create prototypes or product Molds. Detailed and complex designs can be produced with light-induced polymeric reaction printers; the surface of the finished product is smooth, often eliminating the need for grinding; light-induced polymerization models are made with resin, which can be damaged by extending exposition to sunlight; furthermore, printing duration and expenditures are higher than satisfactory; Technical know-how is necessary to operate three-dimensional printers since light-induced polymerization is complex and inappropriate for inexperienced users ^[16].

Stereolithography creates three-dimensional structures by using a computer-controlled laser beam to solidify liquid polymers or resin.30 Compared to earlier forms of other 3DP, stereolithography offers a number of benefits, chief among them being its remarkable resolution and avoidance of heat procedures that may be hazardous to certain drug compounds ^[15].

Charles Hull is regarded as the father of 3D printing as he created, developed, and offered for sale the first 3D printing equipment in the middle of the 1980s.The STL file format works with current CAD programs. Stereolithography (SL), a technique developed by Hull, involves using a laser to cure a liquid resin surface. The stage then undergoes another immersion to allow for the cure of a subsequent layer. Layer by layer, this process is done until the desired shape is reached. The University of Texas at Austin (UT Austin), The company, Massachusetts Institute of Technology (MIT), and other businesses creating innovative additive manufacturing technology were all working on projects concurrently Hull submitted his patent application for his stereolithography, or apparatus (SLA) in the same year that a UT Austin researcher and his advisor submitted a selective laser melting (SLS) patent application. By fusing or sintering a powder bed with a laser beam, decreasing the powder bed, and then applying fresh powder, SLS produces three-dimensional objects. By employing a normal inkjet print head to deposit "ink" or an adhesive solution into a powdered bed, MIT professors created the term "3Dprinter" to refer to a stacking process that binds powder. The process is then repeated layer by layer to obtain the desired shape. The free or nonbonded material that supported [University of Liverpool]'s processing on December 5, 2015, at 23:29. This procedure is commonly referred to as 3D printing. Scott Crump, a co-founder of Stratasys, Ltd., filed a patent application in 1989 on fused deposition modelling (FDM). In this study, we'll call this method 3D powder bed or powder bed inkjet printing. In this process, layers of hardened material are deposited until the required form is achieved. Materials including molten metals, thermoplastic resins, and self-hardening waxes can be employed in this process. Scientists at Helisys, now known as Cubic Technologies, invented the laminated object manufacturing (LOM) process in 1996. Certain materials are piled in sheets that have been formed (typically with lasers) and joined by welding or adhesives ^[25].

Pharmaceutical And Healthcare Uses Of 3D Printing:

Because of its benefits in boosting production efficiency, cutting costs, and removing human error, 3D printing technology is quickly expanding throughout industrial manufacturing industries. In addition to altering industrial output, 3D printing has also shifted the emphasis on industrial automation. This is due to its high degree of adaptability, customization capabilities, and capacity to produce a vast array of forms, ranging from basic to intricate. In order to produce high-quality pharmaceutical products with improved process resilience, the biomedical product development industry, which now relies on manufacturing medicines using traditional manufacturing techniques, is quickly adopting 3D printing. Furthermore, the biomedical engineering of medical devices for therapeutic and diagnostic uses has shown 3D printing to be beneficial. We present an updated evaluation of the previously suggested applications of 3D printing in early-phase drug development, building on earlier studies on medicinal manufacturing and biological applications of 3D printing. The active component needs to be formulated in a practical way so that clinical safety and effectiveness investigations may be carried out in the early stages of drug development" The physiochemical characteristics of the active ingredient must be carefully examined in order to create a dosage form that can be utilized to assess the new medication's therapeutic advantages. Dosage forms may be created by 3D printing at an early stage of drug discovery with minimal time, effort, or financial investment. High dose flexibility and bioavailability features are also provided, which are necessary for formulations created for various patient groups in various geographic locations and to satisfy the requirements of various clinical sites. These features can be printed on dosage forms to support the rapid advancement of clinical trials within a limited time frame" Traditional manufacturing, which is very labour-intensive, costly due to larger batch sizes, and requires extensive preformulation studies to maximize efficiency and ramp up the formula in order to manufacture the requisite dosage forms, does not have these benefits. Specially designed medications The potential of 3D printing to create medications that are specific to patient populations can help individuals or groups receive individualized treatment plans ^[17,18]. Therefore, in addition to treating young and old patients, 3D printing can be a helpful therapeutic tool for treating complex condition including cancer, Alzheimer's disease, and epilepsy. Individualized therapy promises to provide patients the proper dosage at the right time to achieve the best possible drug therapy outcomes and show desired pharmacokinetic (PK) and pharmacodynamic (PD) responses. Furthermore, while designing titration and formulations, these medicines take into account additional variables such body weight, age, gender, and genetic composition. Conventional dose forms, on the other hand, sustain a significant section of the patient population by relying only on a set strength. Furthermore, whereas conventional treatment depends on the creation of a comprehensive production setup with top-tier equipment, 3D printing offers flexibility for on-site fabrication. Therefore, rather of taking a population-centric approach to treatment, 3D printing may encourage an individual-centric one. Complex medication treatment Designing intricate dosage forms with several narrow therapeutic index drug dosages to facilitate long-acting medication therapy may be made easier using 3D printing. In order to sustain blood medication levels for the intended therapeutic impact over an extended period of time, patients frequently need to take many tablets for illness indications when using standard dose forms. Reduced patient compliance, missed doses that cause blood level changes, and high expenses are only a few of the disadvantages of this strategy ^[19,20].

According to reports, three-dimensional printing has a number of benefits over traditional production in the pharmaceutical industry. To start, 3D printing can increase output. In addition to being quicker than conventional techniques, 3D printing offers better resolution, repeatability, accuracy, and consistency when it comes to manufacturing pharmaceutical items like implants and prosthesis. Second, 3D printing may be utilized to make drug dose forms and other individualized and tailored items. Finally, the three-dimensional generated products are reasonably priced. The use of 3D printers is beneficial for small-scale manufacturing enterprises or businesses that create complex items or parts utilized for preoperative planning and customized preoperative treatment because all of its elements are essentially inexpensive. This will result in a multi-step process that determines the optimal therapy approach by combining clinical and imaging data. Numerous studies have shown that individualized pretrial preparation can reduce operating room (OR) time and decrease complications. Additionally, this might lead to cheaper medical costs, shorter reinterventions, and shorter surgical stays ^[21,22,23].

Personalize Surgical Devices And Tools:  Custom surgical tools, guides, and implants may be made via 3D printing. Consequently, cost reductions are achieved by customizing surgical tools and prostheses using the of additive manufacturing. osteoarthritis disorders.3D printing aids in evaluating an individual's response to medicine. Better surgical therapy selection and a more accurate evaluation of the patient's bone health are made possible by this. Enhancing educational opportunities in medicine printed using 3D printer specific to patients’ models have been shown to improve learners' productivity and facilitate rapid learning in the field while also boosting management skills, wisdom, and self-assurance. The ability to model various physiologic and pathologic anatomy from a large dataset of images, the reproducibility and safety of the 3D-printed model in comparison to cadaver breakdown, and the ability to distribute 3D models among institutions—especially those that have limited resources—are some of the benefits of 3D printing in education. To highlight the internal intricacies, 3D printers with a variety of print densities and colours might be utilized ^{[ 24,25,26]}.

3D Printing Technologies In Drug Manufacturing:

The Fourth Industrial Revolution (Industry 4.0) is characterized by the convergence of digital technologies, such as artificial intelligence (AI), the Internet of Things (IoT), and 3D printing, leading to a paradigm shift in manufacturing processes. 3D printing, in particular, holds immense potential to revolutionize drug manufacturing by enabling the production of highly customized and complex drug delivery systems.^{[ 45]}.

Key Advantages Of 3d Printing In Drug Manufacturing:

• Customized Health Care: By enabling the development of customized medication delivery systems that address each patient's unique requirements, 3D printing enhances treatment effectiveness and lowers adverse effects.

• Complicated Compositions: The technique allows for the creation of novel and efficient therapies by producing complex drug formulations with exact control over dose and release patterns ^[27,28].

• Quick Prototyping: By facilitating the quick testing and prototyping of novel formulations and devices, 3D printing speeds up the drug development process.

• Lower Costs: 3D printing may lower production costs and increase efficiency by doing away with the requirement for conventional manufacturing Molds and equipment.

• Better Supply Chain Management: Using 3D printing to produce pharmaceuticals locally can assist to minimize supply chain interruptions and guarantee prompt access to prescription prescriptions

• Drug Distribution Methods: A variety of drug delivery systems, such as tablets, capsules, implants, and patches, with individualized characteristics like dose, release rate, and targeting, may be produced by 3D printing.

• Organ-on-a-Chip Models: Drug development and research can be expedited by using 3D printed organ-on-a-chip models to mimic how the human physique reacts to medications^[29].

Examples Of 3d Printed Drugs-

Spritam (Levetiracetam): The US Food and therapy Agency (FDA) authorized this seizure therapy in 2015, making it the first FDA-approved 3D printed pharmaceutical.

Rheumatoid Arthritis Drug: A clinical trial employing a 3D printed medication for those with rheumatoid arthritis patients was authorized by the FDA in February 2021.

Zip Dose: Aprecia Pharmaceuticals 3D printed tablet technology has been used to create personalized medications with varying release profiles

Oro dispersible Formulations: Researchers have used 3D printing to create rapidly dissolving orodispersible formulations for patients with swallowing difficulties.

Gastro-Retentive Tablets: 3D printing has been used to develop gastro-retentive tablets that can remain in the stomach for extended periods.

Minitablets: Small tablets with exact dosage and regulated distribution profiles are now possible thanks to 3D printing.

Polyprintlets: Researchers have developed flexible multi-drug combinations using 3D printing, allowing for personalized treatment regimens^[30]. These illustrations show how 3D printing technology might be used to create customized pharmaceuticals. with specific release profiles, shapes, and sizes, improving patient compliance and treatment outcomes. In future digital healthcare, individualized characteristics of drug delivery systems will be pretty much highlighted through modernizing already employed and established pharmaceutical production processes. The fundamental basis for implementing such scenarios is the development of internal active feedback between the medicinal product and requirements of every patient^[31]. In this regard, the technology has already shown tremendous promise in delivering personalised drug products either based on the dosage of the medication or on the size and structure of the product. Even though the clinical translation and regulatory framework for 3D-printed pharmaceutical products are still in their infancy, many scenarios that include this incorporation in future healthcare settings have been put up in the literature. This is a review study that will focus mainly on the 3D printing of medication delivery systems. Account being taken of the technology's capacity for controlled release and for adjusting the dose, we provide a summary of the scenarios proposed. Common problems with setting up 3D printers across various sites of production, which include hospitals, community pharmacies, or patient homes. The discussion is the final one addressing scenarios related to current hospital drug shortages, the necessity of a sophisticated networking capability between various production locations, and the paramount importance of establishing a comprehensive regulatory framework. Special patient demographics and polypharmacy response will be considered ^[32].

 
           
       
Figure 8: Braille symbols on 3D-printed oral films (left) and tablets (right) allow visually challenged patients to identify the dose form.

The 3DP technology has been around for some time, but because it is expensive and not cost-effective, there are less successful implementations of this 3DP method in clinical centers and hospitals. Segmentation issues, as well as tough regulatory challenges, are also with the approach. There are currently few studies demonstrating the effectiveness of the 3DP strategy and the significant impact it may have on clinical decision-making and overall results. There are specialized and Randomized case-control research available, the majority which are released in the regions of gastroprotective floating pulsatile delivery systems, retinal vascular disease, and maxillofacial surgery and orthopaedics. Another area with a number of worthwhile research in the interventional and educational domains is cardiology ^[36]. The technique makes it possible to use the product in incredibly tiny batch sizes with highly effective dosage variations for both preclinical research and first-in-human (FIH) studies; Additionally, because the pharmaceutical industry is under pressure to maximize R&D output or to accelerate the rate of commercialization out of the R&D pipelines, it helps to shorten the time period of drug development. Dosing flexibility provides a quick, effective, and accurate way to assess the dose and gather S&E data; products are purchased just before dosing for FIH trials, eliminating storage and shipping. stability testing, which eventually postpones the trials commencement ^[37]. A review of the clinical trial archive gives us information regarding the upcoming 3D-printed goods or technology.  Patents Like the internet and personal computers, 3DP is a disruptive technology, and adopting a disruptive technology is never without its challenges. The Widespread use and technical advancement truly took off in the late 2000s when reasonably priced, high-quality printers were first made generally accessible. To better safeguard manufacturers and customers, significant issues pertaining to 3D-printed medications, such as tort responsibility and property rights, must be resolved. Regulatory issues 3DP is unique among pharmaceutical technologies, and control measures pertaining to process parameters, RMSs, and manufacturing faults require particular attention. Unlike the demands in the case of the other products such as medical equipment, surgeries, training aids, and educational materials, the medication product faces an extremely tough regulatory demand placed on it. In contrast The primary benefit of using proven forms of administration and production procedures/tools is that research on excipient compatibility, drug release, etc. may be completed more quickly in the situation of creating goods without any after marketing statistics or clinical trial experience. In the future, hospital pharmacies and neighborhood pharmacies will play a fundamentally different function, and their inventory management strategies may alter, among other issues pertaining to safety and regulation.They may not have to keep an inventory of drugs (patent and generic) one of the issues critical to the issues of rules regarding the manufacture of drugs by 3D printer is the difference between formulated and manufactured medicines. This question has huge effects on the 3D- printed products the extent of regulation. To share the early thoughts by the FDA on technical factors relating to additively manufactured devices, the USFDA released a guidance in 2017 titled "Technical Considerations for Additive Manufactured Devices." manufacture as well as praise for device testing and characterization. But as of right now, there are no set rules governing medicinal products that are 3D printed. There are a lot of unanswered concerns, including: will the 3D printer, "pharmaceutical ink," and Include the final output in the regulatory process? What regulatory path will the innovators pursue to get such unconventional products? To develop a comprehensive understanding of 3DP, the FDA carries out its own study^[38]. Two Office of Science and Engineering Laboratories (OSEL) labs are heading in the same direction: the FDA's Functional Efficiency and Device Use Laboratory and the Laboratory for Solid Materials. Additional guidelines for the approval of 3D-fabricated goods are provided by medical devices. More than 85 3D-printed implantable and therapeutic items have received FDA approval For FDA clearance, the most often utilized procedures include 510(k), PMA, de novo, HDE, and others. Due to the fact that "3D-printed products are significantly equivalent to a legally marketed device," all approved implants and medical devices created with this technology have so far been approved through the PMN process ^[39]

The following is a regional distribution of clinical trial updates by product.

1. AstraZeneca

2. GlaxoSmithKline

3. Pfizer

4. Merck

5. Johnson & Johnson^[40]

3D printing medications in hospital pharmacies is gaining attention as a viable option. It involves diagnosing patients and tailoring treatments based on individual characteristics. With existing compounding facilities and trained staff, implementing 3D printing for personalized pharmaceuticals appears feasible. Recent studies show promising results; one trial involved treating children with maple syrup urine disease (MSUD) using 3D-printed chewable tablets and hand-filled capsules. The 3D-printed formulations were found to be more acceptable and accurate in dosing, suggesting improvements in quality and safety over traditional methods ^[41].